Variability in the international normalised ratio (INR) in patients with antiphospholipid syndrome and positive lupus anticoagulant: should the INR targets be higher?
ABSTRACT: We present the case of a 34-year-old woman with a history of antiphospholipid syndrome with triple positivity for antiphospholipid antibodies, who had multiple thrombotic events, predominantly pulmonary embolic events, despite treatment with enoxaparin. She is currently on warfarin, with which she has been adequately controlled most of the time, presenting with only one haemorrhagic event consisting of haematuria and prolonged international normalised ratio (INR) without bleeding. This kind of patient represents a challenge for clinicians, particularly due to INR therapeutic targets, which should be higher than recommended in other patients due to the lupus anticoagulant positivity.
Project description:Antiphospholipid syndrome (APS), is an acquired autoimmune disorder characterised by thrombosis, pregnancy morbidity, and the presence of antiphospholipid antibodies (aPL). Although venous thromboembolism is the most common manifestation, thrombotic events in APS may also occur in virtually any vascular bed, with cerebral circulation being the arterial territory most commonly affected. As APS is a heterogeneous condition, its management should be tailored with a patient-centred approach based on individual risk assessment, which includes the aPL profile, concomitant auto-immune diseases, and traditional cardiovascular risk factors. Although literature data are conflicting regarding primary prophylaxis, there is some evidence indicating that antiplatelet agents may reduce the risk of a first thrombotic event in individuals with a high-risk profile. In patients with thrombotic APS, current evidence-based guidelines recommend lifelong vitamin K antagonists (VKAs), preferably warfarin. The optimal intensity of anticoagulation following arterial thrombosis remains controversial. Arterial thrombosis should be treated either with high-intensity warfarin at a target INR > 3.0, or low-dose aspirin (LDA) combined with moderate-intensity warfarin (INR 2.0-3.0). It is recommended to avoid direct oral anticoagulants (DOACs) in patients with high-risk APS, mainly those with triple-positive PL and previous arterial events. They would only be used exceptionally in selected patients with low-risk venous thromboembolism (VTE). In low-risk VTE patients currently treated with a DOAC due to warfarin intolerance or a previous unstable International Normalized Ratio on warfarin, the decision of continuing DOACs would be taken in carefully selected patients. In women with obstetric APS, the combination therapy with LDA plus heparin remains the conventional strategy.
Project description:The present clinical and laboratory classification criteria for antiphospholipid syndrome (APS) were established in Sydney, Australia, in 2006. In this review, we focus on the obstetric subset of APS (OAPS), defined by persistent positivity for antiphospholipid antibodies together with either early recurrent pregnancy loss, early fetal death, stillbirth or premature birth <34 gestational weeks due to pre-eclampsia, eclampsia and placental insufficiency. It is important to diagnose these cases since most women suffering from OAPS can, when given appropriate treatment, have successful pregnancies. Furthermore, patients with OAPS may, depending on the antibody profile, be at enhanced risk of thrombotic events later in life. We present an update on the present knowledge of possible underlying pathogenesis, risk factors and risk estimations for adverse pregnancy outcomes before and during pregnancy, current treatment concepts, and long-term outcomes for women with OAPS and their children.
Project description:We report the clinical case of a nine-year-old girl who presented with progressive motor neuropathy, revealed via the detection of a higher delay in F-wave recording using digitalized nerve conduction/electromyography. Since the lupus anticoagulant (LAC) positivity, detected using diluted Russell viper venom time (dRVVT), switched to persistent serological anticardiolipin immunoglobulin G (IgG) positivity, a possible non-thrombotic antiphospholipid antibody (aPL)-related clinical manifestation was suspected, and intravenous immunoglobulin treatment (IVIG) was started. The IVIG treatment was well tolerated and the complete resolution of motor impairment was obtained after the third IVIG infusion. Our findings suggest that it could be useful to check for antiphospholipid antibodies in children with a rapid onset of progressive neurological signs in order to provide the beneficial use of IVIG in the treatment of pediatric aPL neurological conditions.
Project description:Catastrophic antiphospholipid syndrome is a rare disorder that remains under-recognized causing a high mortality rate even with treatment. Factors such as infections and systemic lupus erythematosus flare play as an inciting event in the thrombotic crisis which underlies catastrophic antiphospholipid syndrome. The use of plasmapheresis has improved the outcome of such cases with a reduction in mortality rate from over 50% to less than 30%, according to some studies. However, the definitive treatment of this disabling and fatal condition remains an area warranting research. Case 1. A case of 32-year-old female with a background of epilepsy and recurrent abortions who presented with difficulty in breathing, dry cough, and bilateral lower limb swelling. The patient initially received treatment with cyclophosphamide and systemic corticosteroids after being diagnosed with systemic lupus erythematosus. She also underwent plasmapheresis for suspected pulmonary hemorrhage as her condition deteriorated rapidly requiring intensive care. The diagnosis was revised as catastrophic antiphospholipid syndrome given the typical multi-organ involvement, namely, cerebritis, Libman-Sacks endocarditis, and nephritis apart from the pulmonary involvement. Eventually, hydroxychloroquine was added to the regimen which led to a remarkable improvement in her condition after a few days. Case 2. A case of 28-year-old female with history of recurrent abortions presented with abdominal pain and was admitted as a case of pancreatitis. The patient received intravenous fluids and analgesics with no significant improvement. Later, she developed multi-organ failure requiring critical care. Given her history and clinical presentation along with the multi-organ involvement in an acute setting, she underwent extensive workup that favored catastrophic antiphospholipid syndrome and she was started on Aspirin initially, and then, hydroxychloroquine was administered. Few days after initiation, her condition improved markedly and with complete resolution of her abdominal symptoms. Hydroxychloroquine's antithrombotic effect in synergy with other therapies has been observed in our cases. Yet, its role in the early course of catastrophic antiphospholipid syndrome merits further investigation.
Project description:Background: The biological diagnostics of antiphospholipid syndrome (APS) takes into account the persistent positivity for anticardiolipin and/or anti-?2GP1 antibodies and/or presence of lupus anticoagulant (LA). However, some non-conventional antiphospholipid antibodies have emerged that could help in the diagnosis of APS. Objectives: To study the potential usefulness of non-conventional antiphospholipid antibodies in clinical practice. Methods: Eighty-seven patients, aged from 15 to 92 years were included and classified in following groups: 41 patients positive for the conventional antibodies with clinical criterion of APS (31 with primary APS and 10 secondary), 17 seronegative APS (SNAPS) patients (i.e., persistent negativity for the conventional antibodies with a strong clinical suspicion of APS), 11 asymptomatic antiphospholipid antibodies carriers (i.e., persistent positivity for the conventional antibodies without clinical evidence of APS), and 18 patients presenting with a first thrombotic or obstetrical event. IgG and IgM were detected to the following antigens: phosphatidylserine/prothrombin (PS/PT) by ELISA, and phosphatidic acid, phosphatidyl-ethanolamine, phosphatidyl-glycerol, phosphatidyl-inositol, phosphatidylserine, annexin V, prothrombin by immunodot. Anti-?2GP1 IgA, and anti-?2GP1 domain 1 IgG were detected by chemiluminescence. Results: Positivity for the non-conventional antibodies was correlated with APS severity; patients with catastrophic APS (CAPS) being positive for 10.7 (Median, Range: 5-14) non-conventional antibodies. 9/17 seronegative patients were positive for at least one of non-conventional antibodies. A study of non-supervised hierarchical clustering of all markers revealed that anti-PS/PT antibodies showed high correlation with the presence of LA. All patients with APS triple positivity (highest risk profile) exhibited also persistent positivity for anti-PS/PT antibodies. Conclusions: Our data obtained from a prospective cohort constituted mainly by patients with primary APS, suggest that non-conventional APS antibodies may be useful for patients classified as SNAPS. They demonstrate the potential value of aPS/PT antibodies as a strong marker of APS. We propose that anti-PS/PT antibodies could be a surrogate APS biological marker of LA to classify in high-risk profile patients treated by direct oral anticoagulants (DOACs), in whom LA detection cannot be achieved.
Project description:OBJECTIVES: To examine the prevalence and associated factors related to the coexistence of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) in a cohort of Colombian patients with SLE, and to discuss the coexistence of APS with other autoimmune diseases (ADs). METHOD: A total of 376 patients with SLE were assessed for the presence of the following: 1) confirmed APS; 2) positivity for antiphospholipid (aPL) antibodies without a prior thromboembolic nor obstetric event; and 3) SLE patients without APS nor positivity for aPL antibodies. Comparisons between groups 1 and 3 were evaluated by bivariate and multivariate analysis. RESULTS: Although the prevalence of aPL antibodies was 54%, APS was present in just 9.3% of SLE patients. In our series, besides cardiovascular disease (AOR 3.38, 95% CI 1.11-10.96, p = 0.035), pulmonary involvement (AOR 5.06, 95% CI 1.56-16.74, p = 0.007) and positivity for rheumatoid factor (AOR 4.68, 95%IC 1.63-14.98, p = 0.006) were factors significantly associated with APS-SLE. APS also may coexist with rheumatoid arthritis, Sjögren's syndrome, autoimmune thyroid diseases, systemic sclerosis, systemic vasculitis, dermatopolymyositis, primary biliary cirrhosis and autoimmune hepatitis. CONCLUSIONS: APS is a systemic AD that may coexist with other ADs, the most common being SLE. Awareness of this polyautoimmunity should be addressed promptly to establish strategies for controlling modifiable risk factors in those patients.
Project description:INTRODUCTION:The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. AIMS:The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. METHODS:Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. DISCUSSION:If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5.
Project description:<h4>Objectives</h4>Antiphosphatidylserine/prothrombin complex antibodies (aPS/PT) are risk factors for thrombosis, yet further validation of their clinical relevance in different ethnic groups is required. We investigated the performance of aPS/PT of IgA/G/M isotypes among Sudanese and Swedish systemic lupus erythematosus (SLE) patients.<h4>Methods</h4>Consecutive SLE patients/matched controls from Sudan (n = 91/102) and Sweden (n = 332/163) were included. All patients fulfilled the 1982 ACR SLE classification criteria. IgA/G/M of aPS/PT, anti-cardiolipin and anti-β<sub>2</sub>glycoprotein I (anti-β<sub>2</sub>GPI) were tested in both cohorts, and lupus anticoagulant (LA) also in the Swedish cohort. Clinical antiphospholipid syndrome-related events and atherosclerosis, measured as carotid plaques were assessed for associations. Univariate and multivariate analyses adjusting for cardiovascular risk factors were performed.<h4>Results</h4>Sudanese SLE patients had higher levels of IgM aPS/PT, but using national cut-offs, the frequency of positivity was similar to Swedish patients for all isotypes. Among Swedish patients, all isotypes of aPS/PT associated with venous thromboembolism (VTE), while only IgA aPS/PT associated with arterial thrombosis (AT). aPS/PT antibodies associated strongly with LA and they were, independently, the best predictor for VTE. Double positivity for aPS/PT and anti-β<sub>2</sub>GPI associated with higher VTE risk than the conventional triple positivity. Carotid plaques did not associate with any antiphospholipid antibody.<h4>Conclusions</h4>IgA aPS/PT associated with AT, and the association of IgG/M aPS/PT with VTE outperforms LA and criteria antiphospholipid antibodies in Swedish SLE patients. Furthermore, double positivity for aPS/PT and anti-β<sub>2</sub>GPI performed better than conventional triple positivity. Future studies need to address if aPS/PT can replace LA, as this would simplify clinical procedures.
Project description:<h4>Purpose of review</h4>Elucidating the pathogenic mechanisms mediated by antiphospholipid antibodies (aPL) might exert important clinical implications in pediatric antiphospholipid syndrome (APS).<h4>Recent findings</h4>aPL are traditionally regarded as the main pathogenic players in APS, inducing thrombosis via the interaction with fluid-phase and cellular components of coagulation. Recent APS research has focused on the role of ?2 glycoprotein I, which bridges innate immunity and coagulation. In pediatric populations, aPL should be screened in appropriate clinical settings, such as thrombosis, multiple-organ dysfunction, or concomitant systemic autoimmune diseases. Children positive for aPL tests often present non-thrombotic non-criteria manifestations or asymptomatic aPL positivity. In utero aPL exposure has been suggested to result in developmental disabilities, warranting long-term follow-up. The knowledge of the multifaceted nature of pediatric APS should be implemented to reduce the risk of underdiagnosing/undertreating this condition. Hopefully, recent pathogenic insights will open new windows of opportunity in the management of pediatric APS.
Project description:International consensus criteria for antiphospholipid syndrome (APS) require persistently positive antiphospholipid antibodies (aPL) and medium or high titers in association with clinical manifestations. However, the clinical relevance of persistence and titers of aPL in patients with stroke has not been identified. We aimed to investigate the risk of subsequent thrombotic events in patients with ischemic stroke with aPL positivity in terms of aPL status.We reviewed the medical records of 99 patients with ischemic stroke with at least one or more aPL-positivity (i.e., positivity for aCL, anti-?2-glycoprotein-1, and/or lupus anticoagulants). The patients were divided into two groups: "definite APS" who fulfilled the laboratory criteria and "indefinite APS" who fell short of the criteria. We compared the risk of subsequent thrombotic events between the two groups. Cox proportional hazards model and Kaplan-Meier survival curves were used for the analyses.Of the 99 patients, 46 (46%) were classified as having definite APS and 53 (54%) as having indefinite APS. The mean follow-up was 51.6 months. Overall event numbers were 14 (30.4%) in definite APS and 16 (30.2%) in indefinite APS. Increased subsequent thrombotic events (hazard ratio 1.039; 95% confidence interval 0.449-2.404; p=0.930) and decreased time to thrombotic events (log-rank p=0.321) were not associated with aPL status.There was no increased risk of subsequent thrombotic events in ischemic stroke patients with definite APS, compared with those with indefinite APS.